EP2463308B1 - Polymer hydrogels and medical use thereof - Google Patents

Polymer hydrogels and medical use thereof Download PDF

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EP2463308B1
EP2463308B1 EP20120158633 EP12158633A EP2463308B1 EP 2463308 B1 EP2463308 B1 EP 2463308B1 EP 20120158633 EP20120158633 EP 20120158633 EP 12158633 A EP12158633 A EP 12158633A EP 2463308 B1 EP2463308 B1 EP 2463308B1
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acid
polymer
polymer hydrogel
carboxymethylcellulose
alkylcelluloses
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EP2463308A1 (en
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Alessandro Sannino
Luigi Ambrosio
Luigi Nicolais
Christian DEMITRI
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Gelesis LLC
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Gelesis LLC
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Priority to HRP20150124TT priority patent/HRP20150124T1/hr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
    • A23L29/262—Cellulose; Derivatives thereof, e.g. ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/225—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B11/00—Preparation of cellulose ethers
    • C08B11/20—Post-etherification treatments of chemical or physical type, e.g. mixed etherification in two steps, including purification
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • C08J3/246—Intercrosslinking of at least two polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/717—Celluloses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/738—Cross-linked polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/005—Crosslinking of cellulose derivatives
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/02—Oxycellulose; Hydrocellulose; Cellulosehydrate, e.g. microcrystalline cellulose
    • C08B15/04—Carboxycellulose, e.g. prepared by oxidation with nitrogen dioxide
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
    • C08J2301/08—Cellulose derivatives
    • C08J2301/26—Cellulose ethers
    • C08J2301/28—Alkyl ethers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
    • Y02E50/00—Technologies for the production of fuel of non-fossil origin
    • Y02E50/30—Fuel from waste, e.g. synthetic alcohol or diesel
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
    • Y02W30/00—Technologies for solid waste management
    • Y02W30/40—Bio-organic fraction processing; Production of fertilisers from the organic fraction of waste or refuse

Definitions

  • the present invention relates to polymer hydrogels and methods of preparation thereof.
  • Polymer hydrogels are cross-linked hydrophilic polymers which are capable of absorbing high amounts of water.
  • cross-linked polymer hydrogels capable of absorbing an amount of water in excess of 10 times their dry weight are defined as "superabsorbent". Some of these materials are even capable of absorbing over 1 litre of water per gram of dry polymer.
  • cross-links or cross-linking knots i.e. the physical or chemical bonds between the macromolecular chains forming the polymer hydrogel network, guarantee the structural integrity of the polymer-liquid system, on the one hand preventing the complete solubilisation of the polymer, and on the other hand allowing the retention of the aqueous phase within the molecular mesh.
  • the superabsorbent polymer hydrogels which are currently available on the market are characterised not only by their marked absorbent properties, but also by their biocompatibility, which is probably due to the high water content, and, above all, by the possibility of adjusting their absorption properties according to the external stimuli. Consequently, such polymer hydrogels may be used as intelligent materials, for example for the manufacture of sensors or actuators for a number of industrial applications.
  • absorbent cores in the field of personal hygiene absorbent products there are more recent and innovative applications such as for example in the biomedical field, for the development of controlled release drug formulations, artificial muscles, sensors, etc., and in agriculture and horticulture, for example in devices for the controlled release of water and nutrients in arid soils.
  • biodegradable polymers used to obtain superabsorbent polymer hydrogels are starch and cellulose derivatives.
  • Anbergen and Oppermann proposed a method for the synthesis of a superabsorbent material made entirely from cellulose derivatives.
  • HEC hydroxyethylcellulose
  • CMCNa carboxymethylcellulose sodium salt
  • the absorption properties of such materials are not high compared to those of the acrylic-based superabsorbent materials.
  • CMCNa may be chemically cross-linked with any reagent which is bifunctional with respect to cellulose.
  • any reagent which is bifunctional with respect to cellulose.
  • divinylsulphone used in the synthetic process according to Anbergen and Opperman
  • epichlorhydrin, formaldehyde and various diepoxides have also been used as cross-linking agents.
  • such compounds are highly toxic in their unreacted states [3].
  • Some carbodiimides are known amongst the unconventional cross-linking agents. Particularly, the use of carbodiimides in order to cross-link salified or non-salified carboxymethylcellulose (CMC) was described in [4].
  • Carbodiimides induce the formation of ester bonds between cellulose macromolecules without participating in the bonds themselves, instead giving rise to a urea derivative having very low toxicity [5].
  • a superabsorbent polymer hydrogel obtained by cross-linking carboxymethylcellulose sodium salt and hydroxyethylcellulose with carbodiimide as the cross-linking agent is disclosed in the international patent application WO 2006/070337 [6].
  • WO 96/02776 discloses polymer hydrogels for use as a delivery matrix or carrier for a biologically active molecule, which hydrogels are obtained by cross-linking hydroxyethylcellulose with citric acid or other oli- or tetracarboxylic acids.
  • the object of the present invention is to provide polymer hydrogels which overcome the above-mentioned disadvantages associated with the use of carbodiimide as a cross-linking agent.
  • the polymer hydrogels of the invention are based on the use of a polycarboxylic acid, such as citric acid, as the cross-linking agent, and in preferred embodiments, also include the use of a molecular spacer.
  • a polycarboxylic acid such as citric acid
  • the present invention provides a polymer hydrogel for use as a medicament, wherein said polymer hydrogel comprises a hydrophilic polymer cross-linked with a polycarboxylic acid selected from C 4 -C 12 - dicarboxylic acids, tricarboxylic acids and tetracarboxylic acids.
  • a polycarboxylic acid selected from C 4 -C 12 - dicarboxylic acids, tricarboxylic acids and tetracarboxylic acids.
  • the invention relates, in part, to the discovery that the cross-linking of soluble cellulose derivatives with citric acid (3-carboxy-3-hydroxy-1,5-pentanedioic acid; hereinafter designated "CA") results in the formation of polymer hydrogels and superabsorbent polymer hydrogels.
  • CA is naturally occurring, non-toxic and available on the market at low cost.
  • CA has been reported as a cross-linking agent for polymers such as cellulose, hydroxypropylmethylcellulose and starch, in textile and food applications [7-11], in these applications CA is used to cross-link and further stabilize insoluble fibers, to provide a fabric with enhanced resiliency and mechanical properties.
  • CA to cross-link carboxymethylcellulose or other soluble hydrophilic polymers for preparing polymer hydrogels and superabsorbent polymer hydrogels has not been previously disclosed.
  • the method of preparing a polymer hydrogel according to the present invention comprises the step of cross-linking an aqueous solution comprising a hydrophilic polymer with a polycarboxylic acid, optionally in the presence of a compound which functions as a molecular spacer.
  • the aqueous solution comprises two or more hydrophilic polymers, such as, for example, hydroxylated polymers.
  • the aqueous solution can comprise a first hydrophilic polymer and a second hydrophilic polymer, which can be present in the same or different amounts on a weight basis.
  • the first hydrophilic polymer is an ionic polymer and the second polymer is a nonionic polymer.
  • Another method for preparing a polymer hydrogel comprises the steps of (a) providing an aqueous solution of carboxymethylcellulose, hydroxyethylcellulose, citric acid and a molecular spacer; (b) heating the aqueous solution, thereby evaporating the water and cross-linking the carboxymethylcellulose and hydroxyethylcellulose to form a polymer hydrogel material; (c) washing the polymer hydrogel material with water or a polar organic solvent to form a washed polymer hydrogel; (d) immersing the washed polymer hydrogel in a cellulose nonsolvent, thereby producing a dried polymer hydrogel;
  • the present invention also provides a polymer hydrogel for use in reducing calorie intake in a subject in need thereof, wherein said polymer hydrogel comprises a hydrophilic polymer cross-linked with a polycarboxylic acid selected from C 4 -C 12 - dicarboxylic acids, tricarboxylic acids and tetracarboxylic acids.
  • a polycarboxylic acid selected from C 4 -C 12 - dicarboxylic acids, tricarboxylic acids and tetracarboxylic acids.
  • the present invention provides polymer hydrogels, and uses thereof.
  • the method of preparing a polymer hydrogel of the present invention comprises the step of cross-linking an aqueous solution comprising a hydrophilic polymer with a polycarboxylic acid, thereby producing the polymer hydrogel.
  • the aqueous solution comprises two or more hydrophilic polymers.
  • the aqueous solution can comprise a first hydrophilic polymer and a second hydrophilic polymer, which can be present in the same or different amounts on a weight basis.
  • the first hydrophilic polymer is an ionic polymer and the second polymer is a nonionic polymer.
  • the cross-linking reaction is preferably conducted at elevated temperature, for example, at a temperature greater than room temperature (25°C).
  • the reaction can be conducted at a temperature from about 30°C to about 150°C, preferably from about 50°C to about 120°C.
  • the reaction solution is concentrated by removal of water. The removal of water can be accomplished, for example, by evaporation. In one embodiment, a fraction of the water is removed. In another embodiment, substantially all of the water is removed, thereby producing a dry residue.
  • the reaction mixture is maintained at elevated temperature for a period of time following removal of water to dryness.
  • hydrophilic polymer refers to a polymer which is substantially water-soluble and, preferably, includes monomeric units which are hydroxylated.
  • a hydrophilic polymer can be a homopolymer, which includes only one repeating monomeric unit, or a copolymer, comprising two or more different repeating monomeric units.
  • the hydrophilic polymer is hydroxylated, such as polyallyl alcohol, polyvinyl alcohol or a polysaccharide. Examples of suitable polysaccharides include substituted celluloses, substituted dextrans, starches and substituted starches, glycosaminoglycans, chitosan and alginates.
  • Polysaccharides which can be used include alkylcelluloses, such as C 1 -C 6 -alkylcelluloses, including methylcellulose, ethylcellulose and n-propylcellulose; substituted alkylcelluloses, including hydroxy-C 1 -C 6 -alkylcelluloses and hydroxy-C 1 -C 6 -alkyl-C 1 -C 6 -alkylcelluloses, such as hydroxyethylcellulose, hydroxy-n-propylcellulose, hydroxy-n-butylcellulose, hydroxypropylmethylcellulose, ethylhydroxyethylcellulose and carboxymethylcellulose; starches, such as corn starch, hydroxypropylstarch and carboxymethylstarch; substituted dextrans, such as dextran sulfate, dextran phosphate and diethylaminodextran; glycosaminoglycans, including heparin, hyaluronan, chondroitin, chondroitin s
  • ionic polymer refers to a polymer comprising monomeric units having an acidic functional group, such as a carboxyl, sulfate, sulfonate, phosphate or phosphonate group, or a basic functional group, such as an amino, substituted amino or guanidyl group.
  • an ionic polymer comprising acidic functional groups will be a polyanion, and such a polymer is referred to herein as an "anionic polymer”.
  • an ionic polymer comprising basic functional groups will be a polycation.
  • ionic polymer such as an "cationic polymer".
  • anionic polymer include alginate, dextran sulfate, carboxymethylcellulose, hyaluronic acid, polyglucuronic acid, polymanuronic acid, polygalacturonic acid, polyarabinic acid; chrondroitin sulfate and dextran phosphate.
  • Suitable cationic polymers include chitosan and dimethylaminodextran.
  • a preferred ionic polymer is carboxymethylcellulose, which can be used in the acid form, or as a salt with a suitable cation, such as sodium or potassium.
  • nonionic polymer refers to a hydrophilic polymer which does not comprise monomeric units having ionizable functional groups, such as acidic or basic groups. Such a polymer will be uncharged in aqueous solution.
  • polycarboxylic acid refers to an organic acid having two or more carboxylic acid functional groups, such as dicarboxylic acids, tricarboxylic acids and tetracarboxylic acids, aand also includes the anhydride forms of such organic acids.
  • Dicarboxylic acids include oxalic acid, malonic acid, maleic acid, malic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, phthalic acid, o-phthalic acid, isophthalic acid, m-phthalic acid, and terephthalic acid.
  • Suitable tetracarboxylic acids include pyromellitic acid, 2,3,3',4'-biphenyltetracarboxylic acid, 3,3',4,4'-tetracarboxydiphenylether, 2,3',3,4'-tetracarboxydiphenylether, 3,3',4,4'-benzophenonetetracarboxylic acid, 2,3,6,7-tetracarboxynaphthalene, 1,4,5,7-tetracarboxynaphthalene, 1,4,5,6-tetracarboxynaphthalene, 3,3',4,4'-tetracarboxydiphenylmethane, 2,2-bis(3,4-dicarboxyphenyl)propane, butanetetracarboxylic acid, and cyclopentanetetracarboxylic acid.
  • a particularly preferred polycarboxylic acid is citric acid.
  • the method can further include the steps of purifying the polymer hydrogel, for example, by washing the polymer hydrogel in a polar solvent, such as water, a polar organic solvent, for example, an alcohol, such as methanol or ethanol, or a combination thereof.
  • a polar solvent such as water
  • a polar organic solvent for example, an alcohol, such as methanol or ethanol, or a combination thereof.
  • the polymer hydrogel immersed in the polar solvent swells and releases any component, such as by-products or unreacted polycarboxylic acid, that was not incorporated into the polymer network.
  • Water is preferred as the polar solvent, distilled water is still more preferred.
  • the volume of water required during this step to reach the maximum swelling degree of the gel is approximately 10- to 20-fold greater than the initial volume of the gel itself.
  • the polymer hydrogel washing step may be repeated more than once, optionally changing the polar solvent employed.
  • the polymer hydrogel can be washed with methanol or ethanol followed by distilled water, with these two steps optionally repeated one or more times.
  • the method can further include drying of the polymer hydrogel.
  • the drying step is carried out by immersing the fully swollen polymer hydrogel in a cellulose nonsolvent, a process known as phase inversion.
  • a cellulose nonsolvent include, for example, acetone and ethanol. Drying the polymer hydrogel by phase inversion results in a final microporous structure which improves the absorption properties of the polymer hydrogel by capillarity. Moreover, if the porosity is interconnected or open, i.e. the micropores communicate with one another, the absorption/desorption kinetics of the gel will be improved as well.
  • acetone/water mixture is formed which increases in water content as the polymer hydrogel dries; at a certain acetone/water concentration, for example, about 55% in acetone, water is no longer able to exit from the polymer hydrogel, and thus fresh acetone has to be added to the polymer hydrogel to proceed with the drying process.
  • acetone/water ratio the faster is the drying process.
  • Pore dimensions are affected by the rate of the drying process and the initial dimensions of the polymer hydrogel particles: larger particles and a faster process tend to increase the pore dimensions; pore dimensions in the microscale range are preferred, as pores in this size range exhibit a strong capillary effect, resulting in the higher sorption and water retention capacity.
  • the cross-linking solution can optionally include a compound which serves as a molecular spacer.
  • a "molecular spacer”, as this term is used herein, is a polyhydroxylated compound which, although not taking part in the reaction resulting in the formation of the cross-linked polymer hydrogel network to a significant extent, results in a polymer hydrogel with an increased absorption capacity. Although in certain cases the molecular spacer may participate in the cross-linking reaction to a small extent, it is believed that molecular spacers function by sterically blocking access to the polymer chains, thereby increasing the average distance between the polymer chains.
  • Suitable compounds for use as molecular spacers in the methods of the present invention include monosaccharides, disaccharides and sugar alcohols, including sucrose, sorbitol, plant glycerol, mannitol, trehalose, lactose, maltose, erythritol, xylitol, lactitol, maltitol, arabitol, glycerol, isomalt and cellobiose.
  • the molecular spacer is preferably included in the cross-linking solution in the amount of about 0.5% to about 10% by weight relative to the solvent, more preferably about 2% to about 8% and more preferably about 4%.
  • the molecular spacer used to synthesise the polymer hydrogel is selected from the group consisting of sorbitol, sucrose and plant glycerol.
  • sorbitol is used as the molecular spacer, at a concentration within the range of 0.5 to 10% by weight referred to the weight of water, preferably within the range of 2 to 8% by weight referred to the weight of water, still more preferably at a concentration of 4% by weight referred to the weight of water.
  • the aqueous solution includes an ionic polymer, preferably an anionic polymer, and most preferably, carboxymethylcellulose.
  • the anionic polymer is carboxymethylcellulose and the polycarboxylic acid is citric acid.
  • the aqueous solution includes an ionic polymer and a non-ionic polymer.
  • the ionic polymer is preferably an anionic polymer, and most preferably, carboxymethylcellulose.
  • the non-ionic polymer is preferably a substituted cellulose, more preferably a hydroxyalkylcellulose or a hydroxyalkyl alkylcellulose, and most preferably hydroxyethylcellulose ("HEC").
  • the preferred polycarboxylic acid is citric acid.
  • the weight ratios of the ionic and non-ionic polymers can range from about 1:10 to about 10:1, preferably from about 1:5 to about 5:1. In preferred embodiments, the weight ratio is greater than 1:1, for example, from about 2 to about 5.
  • the ionic polymer is carboxymethycellulose
  • the non-ionic polymer is hydroxyethylcellulose
  • the weight ratio (ionic:nonionic) is about 3:1.
  • the total precursor concentration in the aqueous solution is of at least 2% by weight referred to the weight of the water of the starting aqueous solution, and the amount of the cross-linking agent is between about 1% and about 5% by weight referred to the weight of the precursor.
  • the term "precursor" indicates the hydrophilic polymer(s) used as the precursors for the formation of the polymer hydrogel polymer network, for example, in certain embodiments the "weight of the precursor” is the weight of CMCNa used or the combined weights of CMCNa and HEC used.
  • the aqueous solution preferably includes sorbitol in an amount of about 4% by weight relative to the weight of water.
  • the cross-linking reaction is preferably carried out at a temperature between about 60°C and 120°C. Varying the temperature during this stage of the process will enable one to increase or decrease the cross-linking degree of the polymer network. A cross-linking temperature of about 80°C is preferred.
  • One particularly preferred method comprises the following steps: Step 1, the hydrophilic polymer(s), the carboxylic acid and, optionally, the molecular spacer are dissolved in water at room temperature; Step 2, the water is removed from the solution at 40°C over a two-day period; Step 3, the product of Step 2 is heated to 80°C for 10 hours to induce the cross-linking reaction and form a polymer hydrogel; Step 4, the polymer hydrogel is washed three times with water over 24 hours; Step 5, the washed polymer hydrogel is immersed in acetone for 24 hours to remove water; Step 6, the polymer hydrogel is further dried in an oven at 45°C for 5 hours; and Step 7, the dried polymer hydrogel is milled to provide polymer hydrogel particles.
  • the present invention also provides polymer hydrogels which can be prepared using the methods of the invention.
  • Such polymer hydrogels comprise a hydrophilic polymer cross-linked with a polycarboxylic acid.
  • the polymer hydrogels of the invention include at least two hydrophilic polymers cross-linked by a polycarboxylic acid.
  • the polymer hydrogel comprises an ionic polymer and a non-ionic polymer and a polycarboxylic acid, preferably a C 4 to C 12 -dicarboxylic acid, a tricarboxylic acid or a tetracarboxylic acid, where the polycarboxylic acid cross-links the ionic polymer and the non-ionic polymer.
  • the weight ratio of ionic polymer to non-ionic polymer is preferably from about 1:5 to about 5:1, more preferably from about 2:1 to about 5:1, and most preferably about 3:1.
  • the ionic polymer is carboxymethylcellulose
  • the non-ionic polymer is hydroxyethylcellulose
  • the polycarboxylic acid is citric acid.
  • the polymer hydrogel comprises an ionic polymer, for example, an anionic polymer or a cationic polymer. More preferably, the ionic polymer is carboxymethylcellulose or a salt thereof, such as sodium carboxymethylcellulose.
  • the polymer hydrogel comprises carboxymethylcellulose cross-linked with citric acid.
  • the polymer hydrogels of the invention have swelling ratios of at least about 5.
  • the polymer hydrogels of the invention are superabsorbent polymer hydrogels, for example, polymer hydrogels having an SR of at least 10.
  • the polymer hydrogels of the invention have SRs at least about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90 or about 100.
  • the polymer hydrogels of the invention have SRs from about 10 to about 100, from about 20 to about 100, from about 30 to about 100, from about 40 to about 100, from about 50 to about 100, from about 60 to about 100, from about 70 to about 100, from about 80 to about 100, or from about 90 to about 100.
  • the invention includes polymer hydrogels having SRs up to 150, 200, 250, 300, 330 or 350.
  • the polymer hydrogels of the invention can absorb an amount of one or more bodily fluids, such as blood, blood plasma, urine, intestinal fluid or gastric fluid, which is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times their dry weight.
  • the ability of the polymer hydrogel to absorb bodily fluids can be tested using conventional means, including testing with samples of bodily fluids obtained from one or more subjects or with simulated bodily fluids, such as simulated urine or gastric fluid.
  • the polymer hydrogels can absorb significant amounts of a fluid prepared by combining one volume of simulated gastric fluid (SGF) with eight volumes of water. SGF can be prepared using USP Test Solutions procedures which are known in the art.
  • the polymer hydrogels of the invention can absorb at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more times their dry weight of this SGF/water mixture.
  • the polymer hydrogels of the invention include cross-linked polymers having varying extents of hydration.
  • the polymer hydrogels can be provided in a state of hydration ranging from a substantially dry or anhydrous state, such as a state in which from about 0% to about 5% of the polymer hydrogel by weight is water or an aqueous fluid, to states comprising a substantial amount of water or aqueous fluid, including up to a state in which the polymer hydrogel has absorbed a maximum amount of water or an aqueous fluid.
  • the polymer hydrogels of the invention can be used in methods for treating obesity, reducing food or calorie intake or achieving or maintaining satiety.
  • the methods comprise the step of administering an effective amount of a polymer hydrogel of the invention to the stomach of a subject, preferably by causing the subject, such as a mammal, including a human, to ingest the polymer hydrogel.
  • Such polymer hydrogels can be used to take up stomach volume, for example, by increasing the volume of a food bolus without adding to the calorie content of the food.
  • the polymer hydrogel can be ingested by the subject prior to eating or in combination with food, for example, as a mixture of the polymer hydrogel with food.
  • the polymer hydrogel Upon ingestion and contact with gastric fluid or a combination of gastric fluid and water, the polymer hydrogel will swell.
  • the polymer hydrogel can be ingested alone or in a mixture with liquid or dry food in a dry, partially swollen or fully swollen state, but is preferably ingested in a state of hydration which is significantly below its fluid capacity, more preferably the polymer hydrogel is ingested in an anhydrous state.
  • the volume of the stomach taken up by the polymer hydrogel can be significantly greater than the volume of the polymer hydrogel ingested by the subject.
  • the polymer hydrogels of the invention can also take up volume and/or exert pressure on the wall of the small intestine by moving from the stomach into the small intestine and swelling.
  • the polymer hydrogel will remain swollen in the small intestine for a period of time sufficient to inhibit the intake of food by the subject, before shrinking sufficiently for excretion from the body.
  • the time sufficient to inhibit the intake of food by the subject will generally be the time required for the subject to eat and for the ingested food to pass through the small intestine, Such shrinking can occur, for example, by degradation through loss of cross-links, releasing fluid and decreasing in volume sufficiently for excretion from the body.
  • Preferred polymers for use in this method exhibit pH-dependent swelling, with greater swelling observed at higher pH than at lower pH.
  • a polymer will not swell significantly in the stomach unless food and/or water is present to raise the pH of the stomach contents and will move into the small intestine.
  • the polymer hydrogel When ingested with food, the polymer hydrogel will initially swell in the stomach, then shrink when the stomach is emptied of food and the pH drops and then move from the stomach to the small intestine. In the higher pH environment of the small intestine the polymer hydrogel will swell, taking up volume in the small intestine and/or exerting pressure on the wall of the small intestine.
  • the polymer hydrogel can optionally be administered in combination with a pH modifying agent, which is an agent which alters the pH of the microenvironment of the polymer hydrogel, thereby modifying its ability to absorb fluids.
  • a pH modifying agent which is an agent which alters the pH of the microenvironment of the polymer hydrogel, thereby modifying its ability to absorb fluids.
  • agents which increase the pH of the microenvironment can increase the swellability of the polymer hydrogel.
  • Suitable pH modifying agents for use with the polymer hydrogels of the invention include buffering agents, H 2 blockers, proton pump inhibitors, anatacids, proteins, nutritional shakes, and combinations thereof.
  • Suitable buffering agents and antacids include ammonium bicarbonate, sodium bicarbonate, calcium carbonate, calcium hydroxide, aluminium hydroxide, aluminium carbonate, magnesium carbonate, magnesium hydroxide, potassium bicarbonate, potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide and combinations thereof.
  • Suitable H 2 blockers include cimetidine, ranitidine, famotidine, nizatidine and combinations thereof.
  • Suitable proton pump inhibitors include omeprazole, lansoprazole, esorneprazole, pantoprazole, abeprazole, and combinations thereof.
  • the present polymer hydrogels can also be used for removing water from the gastrointestinal tract, for example, as a treatment for subjects suffering from kidney disease, including chronic and acute kidney disease, particularly subjects undergoing kidney dialysis.
  • the polymer hydrogels can further be used to modify the fluid content in the gastrointestinal tract of a subject in need thereof, for example, for the treatment of constipation.
  • the invention further provides the use of a polymer hydrogel in the manufacture of a medicament for reducing calorie intake in a subject in need thereof, wherein said polymer hydrogel comprises a hydrophilic polymer cross-linked with a polycarboxylic acid selected from C 4 -C 12 - dicarboxylic acids, tricarboxylic acids and tetracarboxylic acids.
  • a polycarboxylic acid selected from C 4 -C 12 - dicarboxylic acids, tricarboxylic acids and tetracarboxylic acids.
  • the polymer hydrogels of the invention can be used in the manufacture of articles in which polyacrylic polymer hydrogels are conventionally used, in consumer products, such as for example absorbent products for personal care (i.e., babies' napkins, sanitary towels, etc.) and in products for agriculture (e.g., devices for the controlled release of water and nutrients).
  • the absorption properties of the polymer hydrogels of the invention which in some embodiments depend on the amount of carboxymethylcellulose employed and which can be improved by the induction of a microporosity in the gel structure, are comparable to those of polyacrylic gels.
  • the polymer hydrogels obtainable by the method of the present invention therefore possess mechanical properties which make them suitable for use in all of the above-mentioned fields.
  • the present polymer hydrogels have advantages over acrylic polymer hydrogels, such as biodegradability, the absence of any toxic by-products during the manufacturing process and the use of fewer and readily available reagents. Such features enable a real employment of the polymer hydrogels of the invention in the biomedical and pharmaceutical fields as well.
  • polymer hydrogels and superabsorbent polymer hydrogels of the present invention may be used as absorbent materials in the following fields, which are provided by way of non-limiting example:
  • the invention further includes the use of any of the polymer hydrogels of the invention in medicine.
  • Such use includes the use of a polymer hydrogel in the preparation of a medicament for the treatment of obesity or any medical disorder or disease in which calorie restriction has a therapeutic, palliative or prophylactic benefit.
  • CMCNa (MW 700 kDa, DS 0.9, food grade), HEC (MW 250kDa, food grade) were purchased from Eigenmann e Veronelli S.p.A. Milano and citric acid was supplied by Dal Cin S.p.A. Sesto San Giovanni Milano and used as received.
  • Polymer hydrogel samples were obtained by reacting, in water, CMCNa and HEC with citric acid as a cross-linking agent according the following procedure.
  • CMCNa and HEC citric acid as a cross-linking agent
  • a total polymer concentration of 2% by weight of water, using a mixture of CMCNa and HEC, with weight ratio equal to 3/1 was dissolved in distilled water by stirring gently at room temperature until a clear solution was obtained.
  • Poor cross-linking efficiency has been reported if only CMCNa is used, due both to the electrostatic repulsion between polyelectrolyte chains and to the high degree of substitution of hydroxyl groups at C6, the most reactive position [13].
  • CMCNa dissolution is slow at the concentration adopted; thus, first HEC was added to water till, after 5 min, a clear solution was obtained with a slight increase of viscosity; then, CMCNa was added, and the stirring was kept on till a clear solution was obtained (24h), with a significant increase of viscosity. Finally, CA was added at different concentrations (1.75%, 2.75%, 3.75%, 10% and 20% w/w polymer) in order to obtain samples with various degrees of cross-linking. This final solution was used to mold 10 mm thick samples. All samples were first pre-dried at 30°C for 24 h to remove absorbed water and then kept at 80°C for the cross-linking reaction (24h with intermediate control).
  • samples containing neat HEC or neat CMCNa samples cross-linked with CA were also prepared following exactly the same experimental conditions used for HEC/CMCNa mixtures.
  • a differential scanning calorimeter (Mettler-Toledo 822 e Mettler DSC) was used for thermal analysis.
  • the scanning temperature range and the heating rate were 10-200°C and 5°C/min, respectively.
  • the adopted thermal cycle was: (1) heating 10-100°C; (2) isotherm at 100°C for 3 minutes; (3) cooling from 100°C to 10°C; (4) heating from 10°C to 200°C; (5) isotherm at 200°C; (6) cooling until room temperature.
  • An empty pan was used as a reference.
  • FT IR spectra were recorded on a JASCO FT IR 660 plus spectrometer equipped with an attenuated total reflectance (ATR) crystal sampler. Film samples were used directly on a ATR crystal sampler at a resolution of 4 cm -1 , by 300 scans, at absorbance range from 4000 cm -1 to 600 cm -1 .
  • ATR attenuated total reflectance
  • a DSC thermogram of neat citric acid showed a peak at about 60°C, attributable to a water loss process associated with the dehydration leading to an anhydride.
  • CMCNa and HEC powders DSC analysis of neat CMCNa and HEC powders indicates that some water is still absorbed in the polymers. Above 100°C a possible degradation peak of CMCNa is detected. Both CMCNa and HEC show a thermal stability below 100°C.
  • a film of polymer hydrogel obtained using a 3:1 ratio of CMCNa/HEC and 3.75% by weight of polymer of citric acid was analyzed by DSC after drying the sample at 30°C for 24 h and then reduced to powder.
  • a large endothermic peak associated to the evaporation of the water produced by the anhydrification process is evident.
  • a small exothermic peak, attributed to esterification is superimposed on the first one.
  • FT IR spectra were recorded of citric acid, of the A10 reaction mixture before heating and of the A10 reaction mixture after 5 h of heating.
  • the FT IR spectrum of sample A10 shows a strong absorption band at 1590 cm -1 characteristic of cellulose [16]. After heating, the absorbance band at about 1590cm -1 is still observed and additionally a new band at 1738 cm -1 appears.
  • Anhydrides display two stretching bands in the carbonyl region around 1758 cm -1 and 1828 cm -1 .
  • the new peak observed at 1738 cm -1 can be attributed to the characteristic stretching band of the carbonyl group at lower frequency related to anhydride formation, an intermediate reaction necessary for reaction of CA with cellulose hydroxyl groups. In contrast, the carbonyl peak expected at higher frequency is not detectable probably due to its weak intensity.
  • FT IR spectra were recorded of citric acid, B10 reaction mixture before heating and B10 reaction mixture after 6.5 h of heating.
  • the HEC spectrum again shows the band at 1590 cm -1 before and after heating while the absorbance of the carbonyl group at 1738 cm -1 appears only after heating at 80°C as observed for the sample A10.
  • FTIR spectra were also recorded for reactions of HEC polymer when the reaction is performed at 80°C with either 20% CA or 10% CA.
  • the anhydride band intensity increases from 0 to 0.098 when the reaction time increase from 0 h to 6.5 h, but drops to 0 when the reaction time reaches 24 h.
  • the 20% CA reaction follows exactly the same trend providing a maximum value of 0.079 at 5h.
  • the cross-linking mechanism is the same as described for CMCNa
  • the anhydrification and esterification reactions appear superimposed in this case. Therefore, in the FTIR spectra, the HEC polymer shows a single peak. This latter result was in accordance with conclusion of Xie and co-workers [18]. They studied the degree of substitution, as evaluation of cross-linking esterification, on starch thermally reacted with CA at different reaction time and found a maximum after a few hours.
  • CMCNa has carboxylic acid functional groups in its structure that increase the volume variation process in solution.
  • Reaction sample C20 shows similar spectra.
  • polymer mixtures are used (C10 and C20) a broad signal appears at about 1715 cm -1 , especially when a higher CA concentration is used in the reaction.
  • the FT IR spectrum shows a broad band in the range of 1711 cm -1 - 1736 cm -1 and after 13h this band appears more clearly as a narrow absorbance band at 1737 cm -1 , which is typical of carbonyl groups.
  • Spectra of C20 reaction provide similar results. Although a quantitative analysis of carbonyl groups is not possible when C10 and C20 samples are cross-linked, an evaluation of the carbonyl peak similar to those observed for the reaction of the neat polymers can be assumed.
  • the cross-linking kinetics were also monitored studying the swelling behaviour during the reaction progress. Swelling ratio was calculated as a function of the reaction time for: (a) CMCNa with 10% or 20% of CA concentration; (b) HEC with 10% or 20% of CA concentration; (c) the mixture of CMCNa and HEC (3/1) with 10% or 20% CA concentration; (d) the mixture of CMCNa and HEC (3/1) with 1.75%, 2.75% or 3.75% CA concentration.
  • CMCNa/CA sample The maximum swelling of CMCNa/CA sample is observed at the gelation onset, after 3 h, when the second esterification reaction, those leading to cross-linking, begins. Then as the cross-linking process increases the corresponding equilibrium water sorption decreases, confirming the results of FTIR analysis.
  • Polymer hydrogels of practical use presenting a high degree of swelling were obtained with a reduced concentration of citric acid (1.75%, 2.75%, 3.75% by weight of polymer). With a citric acid concentration of 3.75% the swelling ratio can reach 900.
  • This polymer hydrogel, after swelling, is characterized by adequate stiffness and it is able to keep the same shape of the synthesis vat.
  • Polymer hydrogels formerly synthesized [13] using divinyl sulfone, a toxic reagent, as cross-linking agents and the same ratio between CMCNa and HEC were characterized by a maximum swelling ratio of 200. In this case a higher swelling ratio is obtained using an environmentally friendly cross-linking agent. At concentrations lower than 1.75% CA, a weak cross-linking associated with insufficient mechanical property is observed.
  • the cross-linking reaction for CMCNa/HEC system was observed either by DSC or by FTIR analysis.
  • the evolution of the different cross-linking reactions was monitored by means of FT IR spectra collected at different reaction times using an excess of citric acid.
  • An optimal degree of swelling (900) for practical applications was achieved using low CA concentrations.
  • the polymer hydrogel obtained through the method described in this Example 1 has the great advantage to reduce primary and production costs and avoid any toxic intermediate during its synthetic process.
  • the polymer hydrogels were prepared by cross-linking an aqueous solution of carboxymethylcellulose sodium salt (CMCNa) and hydroxyethylcellulose (HEC), using citric acid (CA) as the cross-linking agent and sorbitol as the molecular spacer.
  • CMCNa carboxymethylcellulose sodium salt
  • HEC hydroxyethylcellulose
  • CA citric acid
  • sorbitol sorbitol
  • CMCNa is the ionic polymer species, it is possible to achieve the desired absorption properties adjusting the weight ratio of carboxymethylcellulose sodium salt (CMCNa) to hydroxyethylcellulose (HEC).
  • CMCNa/HEC weight ratio of between 0/1 and 5/1, preferably between 1/1 and 3/1, was observed to enable the synthesis of a polymer hydrogel having optimum absorption properties.
  • Preparation of polymer hydrogel A in a beaker containing distilled water, sorbitol at a concentration of 4% by weight referred to the weight of distilled water was added and mixed until complete solubilisation, which occured within a few minutes.
  • the CMCNa and HEC polymers are added at a total concentration of 2% by weight referred to the weight of distilled water, with a CMCNa/HEC weight ratio of 3/1. Mixing proceeded until solubilisation of the whole quantity of polymer is achieved and the solution became clear.
  • citric acid at a concentration of 1% by weight referred to the weight of the precursor was added to the solution, whose viscosity had greatly increased.
  • Polymer hydrogel B was prepared as polymer hydrogel A, with the only exception that the polymer is made only of CMCNa, and that the CMCNa concentration is 2% by weight referred to the weight of distilled water.
  • Polymer hydrogel C was prepared as polymer hydrogel B, with the only exception that the citric acid concentration is 2% by weight referred to the weight of CMCNa.
  • Polymer hydrogel D was prepared as polymer hydrogel B, with the only exception that the citric acid concentration is 0.5% by weight referred to the weight of CMCNa.
  • the absorption measurements essentially consist of placing the dry sample, obtained from the drying step, in distilled water, so that it swells up until an equilibrium condition is reached.
  • the absorption properties of the gel are assessed based on its swelling ratio (SR), defined according to the formula illustrated above.
  • SR swelling ratio
  • Table 2 below reports some of the results obtained, in terms of the swelling ratio, varying the concentrations of the reagents and the cross-linking times (6 hours, 13 hours, 18 hours, 24 hours).
  • Table 3 shows that the sample having the best swelling ratio is the sample designated as g22, which is characterised by a citric acid (CA) concentration of 1%.
  • CA citric acid
  • Table 4 shows some of the results obtained.
  • the highest swelling ratio is associated with a cross-linking time of 13 hours and a citric acid concentration of 1%. It is also to be noticed that higher citric acid concentrations together with shorter cross-linking times lead to equally satisfactory swelling ratios, although the reaction is very fast and less easy to control.
  • the possibility of increasing the swelling ratio by creating porosity into the material which could promote the absorbing properties was evaluated.
  • the sample g31 subjected to cross-linking for 12 hours, was swelled into distilled water for 24 hours and then dried by phase inversion in acetone. With this technique, a swelling ratio of 200 was obtained.
  • This example describes an evaluation of the superabsorbent polymer hydrogel denoted polymer hydrogel B in Example 2 in in vitro swelling and collapsing experiments in various media at 37°C.
  • SGF simulated gastric fluid
  • SGF was prepared according to USP Test Solutions procedures. The swelling ratio in each fluid was determined at various time points. The results are set forth in Tables 5 and 6. Table 5.
  • This polymer hydrogel swells in simulated gastric fluids (pH 1.5) approximately 15 fold, and in a simulated gastric fluids/water mixture (pH 3) approximately 85 fold. This indicates that the polymer hydrogel has a pH/swelling correlation where at pH below 3 (pKa of CMC is ⁇ 3.1) there will be limited swelling of the polymer hydrogel due to absence of the Donnan effect.
  • the polymer can also swell in the increased pH of simulated intestinal fluid.
  • Figure 2 a graph of cumulative food intake as a function of time, represents a typical study result. There was no difference between the groups at base line. Gavage of 8 mL of polymer hydrogel B induced satiety in the rats that led to a signifient decrease in food intake. As shown in the yellow line, this polymer hydrogel induced a marked decrease in food intake that persisted over 2 hours. These data suggest that polymer hydrogel B can induce satiety in animals and leads to a decrease in food intake.

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JP2010535911A (ja) 2010-11-25
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CA2695974A1 (en) 2009-02-19
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